Doron Schwartz

The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations.

OBJECTIVES This study evaluated the prevalence and severity of anemia in patients with congestive heart failure (CHF) and the effect of its correction on cardiac and renal function and hospitalization. BACKGROUND The prevalence and significance of mild anemia in patients with CHF is uncertain, and the role of erythropoietin with intravenous iron supplementation in treating this anemia is unknown. METHODS In a retrospective study, the records of the 142 patients in our CHF clinic were reviewed to find the prevalence and severity of anemia (hemoglobin [Hb] <12 g). In an intervention study, 26 of these patients, despite maximally tolerated therapy of CHF for at least six months, still had had severe CHF and were also anemic. They were treated with subcutaneous erythropoietin and intravenous iron sufficient to increase the Hb to 12 g%. The doses of the CHF medications, except for diuretics, were not changed during the intervention period. RESULTS The prevalence of anemia in the 142 patients increased with the severity of CHF, reaching 79.1% in those with New York Heart Association class IV. In the intervention study, the anemia of the 26 patients was treated for a mean of 7.2 +/- 5.5 months. The mean Hb level and mean left ventricular ejection fraction increased significantly. The mean number of hospitalizations fell by 91.9% compared with a similar period before the study. The New York Heart Association class fell significantly, as did the doses of oral and intravenous furosemide. The rate of fall of the glomerular filtration rate slowed with the treatment. CONCLUSIONS Anemia is very common in CHF and its successful treatment is associated with a significant improvement in cardiac function, functional class, renal function and in a marked fall in the need for diuretics and hospitalization.

The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study

OBJECTIVES This is a randomized controlled study of anemic patients with severe congestive heart failure (CHF) to assess the effect of correction of the anemia on cardiac and renal function and hospitalization. BACKGROUND Although mild anemia occurs frequently in patients with CHF, there is very little information about the effect of correcting it with erythropoietin (EPO) and intravenous iron. METHODS Thirty-two patients with moderate to severe CHF (New York Heart Association [NYHA] class III to IV) who had a left ventricular ejection fraction (LVEF) of < or =40% despite maximally tolerated doses of CHF medications and whose hemoglobin (Hb) levels were persistently between 10.0 and 11.5 g% were randomized into two groups. Group A (16 patients) received subcutaneous EPO and IV iron to increase the level of Hb to at least 12.5 g%. In Group B (16 patients) the anemia was not treated. The doses of all the CHF medications were maintained at the maximally tolerated levels except for oral and intravenous (IV) furosemide, whose doses were increased or decreased according to the clinical need. RESULTS Over a mean of 8.2+/-2.6 months, four patients in Group B and none in Group A died of CHF-related illnesses. The mean NYHA class improved by 42.1% in A and worsened by 11.4% in B. The LVEF increased by 5.5% in A and decreased by 5.4% in B. The serum creatinine did not change in A and increased by 28.6% in B. The need for oral and IV furosemide decreased by 51.3% and 91.3% respectively in A and increased by 28.5% and 28.0% respectively in B. The number of days spent in hospital compared with the same period of time before entering the study decreased by 79.0% in A and increased by 57.6% in B. CONCLUSIONS When anemia in CHF is treated with EPO and IV iron, a marked improvement in cardiac and patient function is seen, associated with less hospitalization and renal impairment and less need for diuretics.

Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats.

Excess NO generation plays a major role in the hypotension and systemic vasodilatation characteristic of sepsis. Yet the kidney response to sepsis is characterized by vasoconstriction resulting in renal dysfunction. We have examined the roles of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) on the renal effects of lipopolysaccharide administration by comparing the effects of specific iNOS inhibition, -N6-(1-iminoethyl)lysine (L-NIL), and 2,4-diamino6-hydroxy-pyrimidine vs. nonspecific NOS inhibitors (nitro- -arginine-methylester). cGMP responses to carbamylcholine (CCh) (stimulated, basal) and sodium nitroprusside in isolated glomeruli were used as indices of eNOS and guanylate cyclase (GC) activity, respectively. LPS significantly decreased blood pressure and GFR (112+/-4 vs. 83+/-4 mmHg; 2.66+/-0.29 vs. 0. 96+/-0.22 ml/min, P < 0.05) and inhibited the cGMP response to CCh. GC activity was reciprocally increased. L-NIL and 2, 4-diamino-6-hydroxy-pyrimidine administration prevented the decrease in GFR (2.71+/-0.28 and 3.16+/-0.18 ml/min, respectively), restored the normal response to CCh, and GC activity was normalized. In vitro application of L-NIL also restored CCh responses in LPS glomeruli. Neuronal NOS inhibitors verified that CCh responses reflected eNOS activity. L-NAME, a nonspecific inhibitor, worsened GFR (0.41+/-0.15 ml/min), a reduction that was functional and not related to glomerular thrombosis, and eliminated the CCh response. No differences were observed in eNOS mRNA expression among the experimental groups. Selective iNOS inhibition prevents reductions in GFR, whereas nonselective inhibition of NOS further decreases GFR. These findings suggest that the decrease in GFR after LPS is due to local inhibition of eNOS by iNOS, possibly via NO autoinhibition.

The association between congestive heart failure and chronic renal disease.

Purpose of reviewRecent findings on the relationship between congestive heart failure and renal failure are summarized in this review. Recent findingsCongestive heart failure is found in about one-quarter of cases of chronic kidney disease. The most common cause of congestive heart failure is ischemic heart disease. The prevalence of congestive heart failure increases greatly as the patients renal function deteriorates, and, at end-stage renal disease, can reach 65-70%. There is mounting evidence that chronic kidney disease itself is a major contributor to severe cardiac damage and, conversely, that congestive heart failure is a major cause of progressive chronic kidney disease. Uncontrolled congestive heart failure is often associated with a rapid fall in renal function and adequate control of congestive heart failure can prevent this. The opposite is also true: treatment of chronic kidney disease can prevent congestive heart failure. There is new evidence showing the cardioprotective effect of carvedilol in patients on dialysis, and of simvastatin and eplerenone in patients with congestive heart failure. Use of non-steroidal anti-inflammatory drugs doubles the rate of hospitalization in patients with congestive heart failure. Anemia has been found in one-third to half the cases of congestive heart failure, and may be caused not only by chronic kidney disease but by the congestive heart failure itself. The anemia is associated with worsening cardiac and renal status and often with signs of malnutrition. Control of the anemia and aggressive use of the recommended medication for congestive heart failure may improve the cardiac function, patient function and exercise capacity, stabilize the renal function, reduce hospitalization and improve quality of life. Congestive heart failure, chronic kidney disease and anemia therefore appear to act together in a vicious circle in which each condition causes or exacerbates the other. Both congestive heart failure and anemia are often undertreated. Cooperation between nephrologists and other physicians in the treatment of patients with anemic congestive heart failure may improve the quality of care and the subsequent prognosis for both congestive heart failure and chronic kidney disease. SummaryAdequate and early detection and aggressive treatment of congestive heart failure and chronic kidney disease and the associated anemia may markedly slow the progression of both diseases.

Anemia, chronic renal disease and congestive heart failure—the cardio renal anemia syndrome: the need for cooperation between cardiologists and nephrologists

Many patients with congestive heart failure (CHF) fail to respond to maximal CHF therapy and progress to end stage CHF with many hospitalizations, poor quality of life (QoL), progressive chronic kidney disease (CKD) which can lead to end stage kidney disease (ESKD), or die of cardiovascular complications within a short time. One factor that has generally been ignored in many of these people is the fact that they are often anemic. The anemia in CHF is due mainly to the frequently-associated CKD but also to the inhibitory effects of cytokines on erythropoietin production and on bone marrow activity, as well as to their interference with iron absorption from the gut and their inhibiting effect on the release of iron from iron stores. Anemia itself may further worsen cardiac and renal function and make the patients resistant to standard CHF therapy. Indeed anemia in CHF has been associated with increased severity of CHF, increased hospitalization, worse cardiac function and functional class, the need for higher doses of diuretics, progressive worsening of renal function and reduced QoL. In both controlled and uncontrolled studies of CHF, the correction of the anemia with erythropoietin (EPO) and oral or intravenous (IV) iron has been associated with improvement in many cardiac and renal parameters and an increased QoL. EPO itself may also play a direct role in improving the heart unrelated to the improvement of the anemia—by reducing apoptosis of cardiac and endothelial cells, increasing the number of endothelial progenitor cells, and improving endothelial cell function and neovascularization of the heart. Anemia may also play a role in the worsening of acute myocardial infarction and chronic coronary heart disease (CHD) and in the cardiovascular complications of renal transplantation. Anemia, CHF and CKD interact as a vicious circle so as to cause or worsen each other- the so-called cardio renal anemia syndrome. Only adequate treatment of all three conditions can prevent the CHF and CKD from progressing.

Suppression of inducible nitric oxide generation by agmatine aldehyde: Beneficial effects in sepsis

The induction of inducible nitric oxide synthase (iNOS) serves an important immuno‐protective function in inflammatory states, but ungoverned nitric oxide (NO) generation can contribute to a number of pathologic consequences. Delineation of the mechanisms that can downregulate iNOS‐generated NO in inflammation could have therapeutic relevance. Here we show that agmatine, a metabolite of arginine, inhibits iNOS mediated nitric oxide generation in cytokine stimulated cell culture preparations. This effect was not cell type specific. Increased diamine oxidase (DAO) and decreased aldehyde dehydrogenase (AldDH) activities are also representative of inflammatory settings. Increasing the conversion of agmatine to an aldehyde form by addition of purified DAO or suppression of aldehyde breakdown by inhibition of AldDH activity increases the inhibitory effects of agmatine in an additive fashion. Inhibitors of DAO, but not monoamine oxidase (MAO), decreased the inhibitory effects of agmatine, as did the addition of AldDH or reacting aldehydes with phenylhydrazine. We examined rats given lipopolysaccharide (LPS) to evaluate the potential effects of agmatine in vivo. Endotoxic rats administered agmatine prevented the decreases in blood pressure and renal function normally associated with sepsis. Agmatine treatment also increased the survival of LPS treated mice. Our data demonstrate the capacity of agmatine aldehyde to suppress iNOS mediated NO generation, and indicate a protective function of agmatine in a model of endotoxic shock. How agmatine may aid in coordinating the early NO phase and the later repair phase responses in models of inflammation is discussed.

The Interaction between Heart Failure, Renal Failure and Anemia – The Cardio-Renal Anemia Syndrome

Background: Many patients with congestive heart failure (CHF) have chronic kidney insufficiency (CKI) and anemia. Aims: The purpose of this review is to clarify the relationship between these three factors and to study the effect of correction of anemia in CHF and CKI. Findings: Anemia, CHF and CKI are each capable of causing or worsening each other. Thus they form a vicious circle which can result in progressive CHF, CKI and anemia. Aggressive therapy of CHF, CKI and control of the associated anemia with erythropoietin and i.v. iron can prevent the progression of CHF and CKI, reduce hospitalization, and improve quality of life. Conclusion: CHF patients are a major source of end-stage renal failure patients and deserve special attention. If treated well and early, progressive heart failure and renal failure can be prevented. Cooperation between nephrologists, cardiologists, and other internists will improve the care of all three conditions and prevent their progression.

Temporal adjustment of the juxtaglomerular apparatus during sustained inhibition of proximal reabsorption

Tubuloglomerular feedback (TGF) stabilizes nephron function by causing changes in single-nephron GFR (SNGFR) to compensate for changes in late proximal flow (VLP). TGF responds within seconds and reacts over a narrow range of VLP that surrounds normal VLP. To accommodate sustained increases in VLP, TGF must reset around the new flow. We studied TGF resetting by inhibiting proximal reabsorption with benzolamide (BNZ; administered repeatedly over a 24-hour period) in Wistar-Froemter rats. BNZ acutely activates TGF, thereby reducing SNGFR. Micropuncture was performed 6-10 hours after the fourth BNZ dose, when diuresis had subsided. BNZ caused glomerular hyperfiltration, which was prevented with inhibitors of macula densa nitric oxide synthase (NOS). Because of hyperfiltration, BNZ increased VLP and distal flow, but did not affect the basal TGF stimulus (early distal salt concentration). BNZ slightly blunted normalized maximum TGF response and the basal state of TGF activation. BNZ sensitized SNGFR to reduction by S-methyl-thiocitrulline (SMTC) and caused the maximum TGF response to be strengthened by SMTC. Sensitization to type I NOS (NOS-I) blockers correlated with increased macula densa NOS-I immunoreactivity. Tubular transport measurements confirmed that BNZ affected TGF within the juxtaglomerular apparatus. During reduced proximal reabsorption, TGF resets to accommodate increased flow and SNGFR through a mechanism involving macula densa NOS.

Effects of Treatment with Epoetin Beta on Outcomes in Patients with Anaemia and Chronic Heart Failure

Anaemia is frequently found in patients with chronic heart failure (CHF) and has been associated with an increase in mortality and morbidity, impaired cardiac and renal function and a reduced quality of life (QoL) compared with non-anaemic CHF patients. Correction of anaemia with recombinant human erythropoietin (epoetin) has been associated with an improvement in CHF in both controlled and uncontrolled studies. The present study describes our findings in a series of 78 consecutive patients with symptomatic CHF and anaemia (haemoglobin (Hb) level <12.0 g/dl) treated with epoetin beta and, if necessary, intravenous iron sucrose. Over a mean observation period of 20.7 ± 12.1 months, mean Hb levels increased from 10.2 ± 1.1 to 13.5 ± 1.2 g/dl, p < 0.01. New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF) were significantly improved and the number of hospitalizations was significantly reduced with the period before treatment (all p < 0.01). Serum creatinine and creatinine clearance (CCr) were 2.2 ± 0.9 mg/dl and 32.5 ± 26.5 ml/min, respectively, at baseline, and remained stable over the observation period. Interestingly, >90% of the patients had concomitant mild-to-moderate chronic kidney disease at baseline and study end (CKD), as defined by the accepted diagnostic criterion of a CCr <60 ml/min. Conclusions: The correction of the anaemia with epoetin beta together with initial intravenous iron supplementation, resulted in significant improvements in NYHA class and cardiac function, and a reduction in hospitalization rate. Moreover, renal function was maintained stable in most patients.

Secondary Prevention of Hyperkalemia With Sodium Polystyrene Sulfonate in Cardiac and Kidney Patients on Renin‐Angiotensin‐Aldosterone System Inhibition Therapy

Hyperkalemia, induced by renin‐angiotensin‐aldosterone system inhibition (RAAS‐I) in patients with chronic kidney disease (CKD), or cardiac disease often leads to withdrawal of RAAS‐I therapy. Sodium polystyrene sulfonate (SPS) is a potassium‐binding resin used for the treatment of hyperkalemia. Recently, concerns about the safety and efficacy of SPS were raised. We report here a follow‐up of 14 patients with CKD and heart disease on RAAS‐I treatment who were treated with low‐dose daily SPS to prevent recurrence of hyperkalemia.